Redox regulation of interleukin-4 signaling.
The physiologic control of cytokine receptor activation is primarily mediated by reciprocal activation of receptor-associated protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Here, we show that immediately after ligand-dependent activation, interleukin (IL)-4 receptor generated reactive oxygen species (ROS) via phosphatidylinositol 3-kinase-dependent activation of NAD(P)H oxidase (NOX)1 and NOX5L. ROS, in turn, promoted IL-4 receptor activation by oxidatively inactivating PTP1B that physically associated with and deactivated IL-4 receptor. However, ROS were not required for the initiation of IL-4 receptor activation. ROS generated by other cytokine receptors, including those for erythropoietin, tumor necrosis factor-alpha, or IL-3, also promoted IL-4 signaling. These data indicate that inactivation of receptor-associated PTP activity by cytokine-generated ROS is a physiologic mechanism for the amplification of cytokine receptor activation in both cis and trans, revealing a role for ROS in cytokine crosstalk.
Sharma
Pankaj
P
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Chakraborty
Rikhia
R
Wang
Lu
L
Min
Booki
B
Tremblay
Michel L
ML
Kawahara
Tsukasa
T
Lambeth
J David
JD
Haque
S Jaharul
SJ
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000378:metabolism*; D015398:Signal Transduction
D015847:Interleukin-4; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017382:Reactive Oxygen Species; D011972:Receptor, Insulin; D019948:Receptors, Interleukin-4; C081827:insulin receptor serine kinase